1. Field of the Invention
This invention resides in the field of topical compositions for use in treating lips suffering from cracking, fissuring, or scaling as a result of xeric stress, and for preventing the occurrence of such conditions.
2. Description of the Prior Art
The lips are a mucosal epithelium, unique among other mucosal tissues because the constant exposure of the lips to the environment requires the lips to function as epidermal tissue. Lips demonstrate a less efficient barrier function than other epidermal tissues, however, and are therefore more susceptible to moisture loss and the detrimental effects that result from xeric stress.
This invention arises from the discovery that a reason for the inability of the lips to provide an efficient barrier function is that they are low in certain lipid processing enzymes that are needed to generate some of the lipids that contribute to an effective barrier function. In particular, the lips have relatively low levels of endogenous xcex2-cerebrosidase and phospholipases, and accordingly the lips contain relatively large amounts of glucosylceramides and phospholipids that have not been converted by these enzymes to ceramides and free fatty acids. Since the resulting lipid mixture is low in its levels of these lipids, it is not an efficient composition for supporting the barrier function. This renders hence lips more susceptible to dehydration, which leads to cracking, fissuring and scaling.
In accordance with this invention, therefore, it has been discovered that xeric stress of the lips can be treated or prevented by the application of any of several topical formulations, as follows:
(1) Formulations in which the only lipids included in the formulations that are physiologically active in affecting the moisture content of the lips are:
(a) one or more ceramides,
(b) one or more essential free fatty acids, and
(c) one or more nonessential free fatty acids; and
(2) Formulations that contain:
(a) a xcex2-glucocerebrosidase or an analog thereof that has substantially similar activity in converting glucosylceramides to ceramides, and/or
(b) a phospholipase A2 or an analog thereof that has substantially the same activity in converting phospholipids to free fatty acids.
The term xe2x80x9cceramidesxe2x80x9d refers to a class of compounds that are otherwise known as xe2x80x9csphingoidxe2x80x9d compounds or xe2x80x9csphingolipids.xe2x80x9d These compounds have a backbone of sphingosine or a closely related structure, with fatty acids linked to the backbone through an amide linkage at the amino group of the sphingosine structure. The generic formula for ceramides is as follows: 
in which:
R1 is alkyl or xcex1-hydroxyalkyl;
R2 is either 
R3 is C10-C20 alkyl.
The term xe2x80x9calkylxe2x80x9d as it is used herein includes both straight-chain and branched-chain groups, saturated and unsaturated (i.e., containing one or more double bonds), and monovalent or divalent as indicated by the position of the group in the structural formula. Straight-chain groups are generally preferred. The term xe2x80x9cxcex1-hydroxyalkylxe2x80x9d as it is used herein refers to groups derived from xcex1-hydroxy fatty acids, the xcex1-position denoting the carbon adjacent to the carboxyl group of the fatty acid. By xe2x80x9cfatty acid residuexe2x80x9d is meant the portion of a fatty acid remaining after removal of the xe2x80x94COOH group.
Preferred groups for R1 are C10-C36 alkyl and xcex1-hydroxy-C10-C36 alkyl, or either of the two subgroups C14-C20 alkyl and xcex1-hydroxy-C14-C20 alkyl or C20-C36 alkyl and xcex1-hydroxy-C20-C36 alkyl. Particularly preferred are C20-C36 alkyl, and the most preferred are saturated C20-C36 alkyl.
The preferred group for R2 is 
Preferred groups for R3 are C12-C16 saturated straight-chain alkyl, particularly C13-C15 saturated straight-chain alkyl, with C13 and C15 saturated straight-chain alkyl as the most preferred.
Many ceramides are naturally occurring in certain plant tissues such as yeast, and also in the mammalian stratum corneum and in other mammalian tissues such as brain tissue and nervous tissue. Ceramides can be extracted from these tissues by methods known in the art. Bovine brain tissue and human spleen tissue are common commercial sources. A mixture termed xe2x80x9cceramides type IIIxe2x80x9d is prepared by the action of phospholipase C on bovine brain sphingomyelin, and the R3 moiety is primarily stearic (saturated 18-carbon) and nervonic (unsaturated 24-carbon) acids. A mixture termed xe2x80x9cceramides type IVxe2x80x9d is similar to ceramides type III except that it contains xcex1-hydroxy acids rather than stearic and nervonic acids. Both mixtures are commercially available from chemicals suppliers such as Sigma Chemical Company, St. Louis Mo., USA, and those which are not direct extracts are capable of being prepared by techniques described in the literature, such as Morrison, W. R., Biochem. Biophys. Acta 176:537 (1979), and Carter, H. E., et al., J. Lipid Res. 2:228 (1961). In general, seven types of ceramides are known, and all are believed to be useful in the practice of this invention.
The components designated herein as xe2x80x9cfree fatty acidsxe2x80x9d include xcex1-hydroxy fatty acids and xcfx89-hydroxy fatty acids, and non-hydroxylated fatty acids, both saturated and unsaturated, and both straight-chain and branched-chain. Straight-chain, xcex1-hydroxy and non-hydroxylated fatty acids are preferred. The fatty acids are generally up to 36 carbon atoms in length. Preferred lengths are 12 to 20 carbon atoms.
The essential free fatty acids are linoleic acid (18 carbon atoms, two double bonds) and linolenic acid (18 carbon atoms, three double bonds), including the various isomers of these acids. Nonessential free fatty acids are all other fatty acids, notably those of 12 to 20 carbon atoms. Preferred nonessential free fatty acids are those of 16 to 18 carbon atoms, and the most preferred are stearic and palmitic acids. The free fatty acids may also be supplied in the form of their glycolipid precursors such as triglycerides.
The enzyme xcex2-glucocerebrosidase (xcex2-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of glucocerebrosides to glucose and ceramides. This enzyme is a naturally occurring human enzyme that is available from commercial suppliers. Certain analogues of the enzyme with similar activity are also commercially available and can likewise be used in this invention. One such analogue is CEREZYME(copyright), which is produced by recombinant DNA technology using mammalian cell culture. This analogue, which is also known is imiglucerase, is a momeric glycoprotein of 497 amino acids, differing from placental glucocerebrosidase by the substitution of histidine for arginine at position 495, and by the modification of the oligosaccharide chains at the glycosylation sites such that they terminate in mannose sugars. Another analogue is CEREDASE(copyright) (alglucerase), produced by modification of the oligosaccharide chains of human xcex2-glucocerebrosidase to alter the sugar residues at the non-reducing ends so that they are predominantly terminated with mannose residues. Each of these analogues is available from Genzyme Corporation, Cambridge, Mass., USA.
Phospholipase A2 is a class of enzymes that specifically catalyzes the hydrolysis of the sn-2 acyl or alkyl ester of phosphoglycerides, producing equimolar quantities of lysophospholipids and free fatty acids. Preferred phospholipase A2 (PLA2) enzymes for use in this invention are mammalian secretory PLA2 enzymes and particularly pancreatic Type 1 or Type 5 secretory PLA2 enzymes. Porcine, bovine and human pancreatic PLA2 are commercially available from chemical suppliers, such as Sigma Chemical Company, St. Louis, Mo., USA.
The enzymes xcex2-glucocerebrosidase (or its analogs) and secretory phospholipase A2 can also be applied individually rather than in combination. Application of either one individually will provide partial relief of xeric stress.
In each of the formulations of this invention, the relative amounts of the components may vary and specific proportions are not critical to the invention. In each case, however, certain ranges of proportions are preferred. For the formulations described herein as containing a combination of (a) ceramide, (b) essential free fatty acid, and (c) nonessential free fatty acid, the preferred mole ratios of (a):(b):(c) are about (1-5):(1-5):(1-5). A more preferred mole ratio range is about (1-3):(1-3):(1-3). Alternatively, preferred ratios are those that combine with the cholesterol already present in the lips stratum corneum to achieve a final lipid composition in which the mole ratio of (cholesterol):(ceramide):(essential free fatty acid):(nonessential free fatty acid) is from about 1:1:1:1 to about 3:1:1:1.
The compositions of this invention are applied directly to the lips, and may be incorporated in a cosmetic preparation such as lipstick or a therapeutic or preventive preparation such as lip balm. The preparation may take various forms such as a stick, salve, cream or ointment. The preparations will generally include a vehicle, and any non-toxic and pharmaceutically acceptable vehicle, including those that are known for use in application to lips may be used. Examples are petrolatum, mineral oil, modified or unmodified vegetable oils, silicon-based oils and other synthetic oils, and waxes. Additional ingredients such as pigments, perfumes, sunscreens, and preservatives may also be included.